POS1423 ASSESSING THE EFFECT OF ANTIHYPERTENSIVE DRUGS ON SYSTEMIC LUPUS ERYTHEMATOSUS： A MENDELIAN RANDOMIZATION STUDY
Authors: Y. Lu, Z. Zhao, S. Song, J. Qiao, S. X. Zhang, X. LI
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease characterized by autoantibody production and multisystem inflammation. Alpha-adrenoceptor blockers(AAB), angiotensin converting enzyme inhibitors(ACEI), beta-adrenoceptor blockers(BB) and calcium channel blockers(CCB) are common antihypertensive drugs. However, data on their relative impact on Systemic lupus erythematosus (SLE) are limited. We leveraged genetic variants mimicking AAB, ACEI, CCB and BB antihypertensive drugs to investigate their effects on risk of SLE using the Mendelian randomization. <h3>Objectives</h3> This study aims to assess the causal association between AAB, ACEI, BB and CCB and SLE disease within a Mendelian-randomization design. <h3>Methods</h3> The significant single-nucleotide polymorphisms(SNPs) associated with SLE were obtained from the UK Biobank, including 14,267 individuals of European ancestry (5,201 cases and 9,066 controls) <sup>[1]</sup>. Blood pressure data were retrieved from the International Consortium of Blood Pressure(ICBP) Genome-Wide Association Studies <sup>[2]</sup>. For each drug target, SNPs in the drug target gene region(± 100kb) that were associated with SBP (p &lt; 5 × 10<sup>−8</sup>) were selected as proxies for drug target perturbation after clumping to a pairwise linkage disequilibrium threshold of r<sup>2</sup> &lt; 0.3. If we do not find the corresponding snp, we select SNPs in the drug target gene region (± 1mb) after clumping to a pairwise linkage disequilibrium threshold of r<sup>2</sup> &lt; 0.8. If there was only a single variant available, we used the Wald ratio to estimate the effect. For the rest, MR was performed using inverse variance weighting (IVW), MR-Egger and Weighted median methods. <h3>Results</h3> Genetically-proxied AAB was associated with reduced risk of systemic lupus erythematosus (OR = 0.91, 95% CI = 0.87 - 0.95, P = 4.1 × 10<sup>−5</sup>). Genetically-proxied ACEI, BB and CCB were not associated with systemic lupus erythematosus: ACEI(OR=1.07, 95% CI= 0.83-1.37, P = 0.60), BB(OR = 0.99, 95% CI = 0.92 - 1.07, P = 0.96, CCB(OR = 0.99, 95% CI = 0.96 - 1.02, P = 0.87), CCB(OR = 0.99, 95% CI = 0.96 - 1.02, P = 0.87). Genetically-proxied overall antihypertensive was associated with reduced risk of systemic lupus erythematosus(OR = 0.96, 95% CI = 0.93 - 0.98, P = 7.8 × 10<sup>−4</sup>). <h3>Conclusion</h3> Mendelian randomization suggests that antihypertensive drugs is likely to affect the risk of developing systemic lupus erythematosus. We found that the effect of the risk of developing systemic lupus erythematosus is different by using antihypertensive drugs. So, for systemic lupus erythematosus patients with hypertension, we give priority to Alpha-adrenoceptor blockers to lower blood pressure. <h3>References</h3> [1]Ardissino, M.; Slob, E. A. W.; Rajasundaram, S.; Reddy, R. K.; Woolf, B.; Girling, J.; Johnson, M. R.; Ng, F. S.; Gill, D., Safety of beta-blocker and calcium channel blocker antihypertensive drugs in pregnancy: a Mendelian randomization study. BMC medicine 2022, 20 (1), 288. [2]Bentham, J.; Morris, D. L.; Graham, D. S. C.; Pinder, C. L.; Tombleson, P.; Behrens, T. W.; Martín, J.; Fairfax, B. P.; Knight, J. C.; Chen, L.; Replogle, J.; Syvänen, A. C.; Rönnblom, L.; Graham, R. R.; Wither, J. E.; Rioux, J. D.; Alarcón-Riquelme, M. E.; Vyse, T. J., Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nature genetics 2015, 47 (12), 1457-1464. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.